Method for the synthesis of phosphorus atom modified nucleic acids

a technology of phosphorus atoms and nucleic acids, applied in the field of methods of synthesizing phosphorous atommodified nucleic acids, can solve the problems of limited use of natural sequences of dna or rna

Active Publication Date: 2016-07-19
WAVE LIFE SCI LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Benefits of technology

[0089]The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:

Problems solved by technology

The use of natural sequences of DNA or RNA is limited by their stability to nucleases.

Method used

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  • Method for the synthesis of phosphorus atom modified nucleic acids
  • Method for the synthesis of phosphorus atom modified nucleic acids
  • Method for the synthesis of phosphorus atom modified nucleic acids

Examples

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example 1

Solution Synthesis of a Phosphorothioate Dimer, (SP)-1,8-Diazabicyclo[5.4.0]undec-7-enium N3-benzoyl-5′-O-(tert-butyldiphenylsilyl)thymidin-3′-yl N3-benzoyl-3′-O-(tert-butyldimethylsilyl)thymidin-5′-yl phosphorothioate [(SP)-4tt] via Route A

[0496]8-Diazabicyclo[5.4.0]undec-7-enium N3-benzoyl-5′-O-(tert-butyldiphenylsilyl)thymidin-3′-yl phosphonate (1t) (96.0 mg, 120 μmol) was dried by repeated coevaporations with dry pyridine and then dissolved in dry pyridine (2 mL). BTC (29.7 mg 100 mmol) was added, and the mixture was stirred for 10 min. An aminoalcohol L-2 (21.3 mg, 120 μmol) solution, which was prepared by repeatedly coevaporations with dry pyridine and dissolved in dry pyridine (1 mL), was added to the reaction mixture dropwise via syringe, and the mixture was stirred for 5 min under argon atmosphere. To the solution of N3-benzoyl-3′-O-(tert-butyldimethylsilyl)thymidine (3t), which was prepared by repeated coevaporations with dry pyridine and dissolved in pyridine (500 μmol), ...

example 2

Solution Synthesis of a Phosphorothioate Dimer, (SP)-1,8-Diazabicyclo[5.4.0]undec-7-enium 6-N-benzoyl-5′-O-(tert-butyldiphenylsilyl)-deoxyadenosin-3′-yl 3′-O-(tert-butyldimethylsilyl)thymidin-5′-yl phosphorothioate [(SP)-4at] via Route A

[0498](SP)-4at is obtained from 1,8-diazabicyclo[5.4.0]undec-7-enium 6-N-benzoyl-5′-O-(tert-butyldiphenylsilyl)-deoxyadenosin-3′-yl phosphonate (1a) instead of 1t, using the reaction steps described above for (SP)-4tt.

example 3

Solution Synthesis of a Phosphorothioate Dimer, (SP)-1,8-Diazabicyclo[5.4.0]undec-7-enium 4-N-benzoyl-5′-O-(tert-butyldiphenylsilyl)-deoxycytidin-3′-yl 3′-O-(tert-butyldimethylsilyl)thymidin-5′-ylphosphorothioate [(SP)-4ct] via Route A

[0499](SP)-4ct is obtained from 1,8-diazabicyclo[5.4.0]undec-7-enium 4-N-benzoyl-5′-O-(tert-butyldiphenylsilyl)-deoxycytidin-3′-yl phosphonate (1c), instead of 1t, using the reaction steps described above for (SP)-4tt.

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Abstract

Described herein are methods of syntheses of phosphorous atom-modified nucleic acids comprising chiral X-phosphonate moieties. The methods described herein provide backbone-modified nucleic acids in high diasteteomeric purity via an asymmetric reaction of an achiral molecule comprising a chemically stable H-phophonate moiety with a nucleoside / nucleotide.

Description

FIELD OF THE INVENTION[0001]Described herein are methods of syntheses of phosphorous atom-modified nucleic acids comprising chiral X-phosphonate moieties. The methods described herein provide backbone-modified nucleic acids in high diastereomeric purity via an asymmetric reaction of an achiral molecule comprising a chemically stable H-phosphonate moiety with a nucleoside / nucleotide.BACKGROUND OF THE INVENTION[0002]Oligonucleotides are useful in therapeutic, diagnostic, research, and new and nanomaterials applications. The use of natural sequences of DNA or RNA is limited by their stability to nucleases. Additionally, in vitro studies have shown that the properties of antisense nucleotides such as binding affinity, sequence specific binding to the complementary RNA, stability to nucleases are affected by the configurations of the phosphorous atoms. Therefore, there is a need in the field for methods to produce oligonucleotides which are stereocontrolled at phosphorus and exhibit desi...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): C07H21/00C07H21/02C07H21/04C12Q1/68
CPCC07H21/00C07H1/00
Inventor WADA, TAKESHISHIMIZU, MAMORU
Owner WAVE LIFE SCI LTD
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